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J. Biol. Chem., Vol. 283, Issue 37, 25557-25566, September 12, 2008

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ERp16, an Endoplasmic Reticulum-resident Thiol-disulfide Oxidoreductase

BIOCHEMICAL PROPERTIES AND ROLE IN APOPTOSIS INDUCED BY ENDOPLASMIC RETICULUM STRESS^*

Woojin Jeong, Duck-Yeon Lee, Sunjoo Park, and Sue Goo Rhee¹

From the Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea and the Laboratory of Biochemistry, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

We have characterized the properties and putative role of a mammalian thioredoxin-like protein, ERp16 (previously designated ERp18, ERp19, or hTLP19). The predicted amino acid sequence of the 172-residue human protein contains an NH₂-terminal signal peptide, a thioredoxin-like domain with an active site motif (CGAC), and a COOH-terminal endoplasmic reticulum (ER) retention sequence (EDEL). Analyses indicated that the mature protein (comprising 146 residues) is generated by cleavage of the 26-residue signal peptide and is localized in the lumen of the ER. Biochemical experiments with the recombinant mature protein revealed it to be a thioldisulfide oxidoreductase. Its redox potential was about -165 mV; its active site cysteine residue Cys⁶⁶ was nucleophilic with a pK_a value of 6.6; it catalyzed the formation, reduction, and isomerization of disulfide bonds, with the unusual CGAC active site motif being responsible for these activities; and it existed as a dimer and underwent a redox-dependent conformational change. The observations that the redox potential of ERp16 (-165 mV) was within the range of that of the ER (-135 to -185 mV) and that ERp16 catalyzed disulfide isomerization of scrambled ribonuclease A suggest a role for ERp16 in protein disulfide isomerization in the ER. Expression of ERp16 in HeLa cells inhibited the induction of apoptosis by agents that elicit ER stress, including brefeldin A, tunicamycin, and dithiothreitol. In contrast, expression of a catalytically inactive mutant of ERp16 potentiated such apoptosis, as did depletion of ERp16 by RNA interference. Our results suggest that ERp16 mediates disulfide bond formation in the ER and plays an important role in cellular defense against prolonged ER stress.

Received for publication, May 19, 2008 , and in revised form, July 8, 2008.

^* This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by Bio R&D Program Grants M10642040002-07N4204-00210 (to W. J.) and M10642040001-07N4204-00110 (to S. G. R.), National Honor Scientist Program Grant R09-2006-000-10002-0 (to S. G. R.), and National Core Research Center Program Grant R15-2006-020 (to W. J.) through the Korea Science and Engineering Foundation funded by the Ministry of Education, Science, and Technology, and by the Brain Korea 21 Scholars Program (to S. P). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Life and Pharmaceutical Sciences, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Korea. Tel.: 82-2-3277-2948; Fax: 82-2-3277-3760; E-mail: rheesg{at}ewha.ac.kr.

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